Propoxyphene hydrochloride, named in the U.S. Pharmacopeia XVIII, page 556 as (+)-.alpha.-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate hydrochloride or by Poland and Sullivan, J. Am. Chem. Soc., 77, 3400 (1955) as .alpha.-d-4-dimethylamino-1,2-diphenyl-3-methyl-2-propionyloxybutane hydrochloride, has been marketed for many years as a potent analgesic of low physical dependance liability. The corresponding racemate, .alpha.-dl-4-dimethylamino-1,2-diphenyl-3-methyl-2-propionyloxybutane, was prepared by Poland and Sullivan, J. Am. Chem. Soc., 75, 4458 (1953). Pharmacology of the racemate was reported by Robbins, J. Am. Pharm. Soc., 44 497 (1955) who determined that, by the subcutaneous route, the analgesic dosage of the racemate was in the range 10-20 mg./kg. Generally, the analgesic potency of the racemate was taken to be equal to about half that of codeine. Miller et al., J. Pharm. Sci., 52, 446 (1963) reported on both the analgesic and antitussive potency by parenteral administration for the racemic compound as well as other closely related derivatives. It was reported by Poland and Sullivan, J. Am. Chem. Soc., 77, 3400 (1955), however, that the pure .alpha.-d-isomer-(+)-d-4-dimethylamino-1,2-diphenyl-2-butanol propionate was responsible for the analgesic activity of the .alpha.-dl-mixture in that 10 mg/kg. of the .alpha.-d-isomer produced an analgesic effect equal to that of 20 mg/kg. of the racemate when administered subcutaneously. They also reported that the .alpha.-1-isomer gave no response with subcutaneous doses from 10 to 80 mg./kg. Gruber, J. Lab. Clin. Med. 44, 805 (1954) reported on the administration of the racemate, named by him 1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane hydrochloride, in humans by the oral route. It was his conclusion that 80 mg. of the racemate was equivalent to 325 mg. of aspirin and 50 mg. was equivalent to 32.5 mg. of codeine phosphate. Currently, propoxyphene hydrochloride (the pure d-isomer) is sold in single dosage forms containing 32 or 65 mg. of drug. Codeine sulfate is currently marketed in 15, 30 and 60 mg. tablets.
Cooper and Anders, reporting in Life Sciences, 15, 1665 (November, 1974), stated that administration subcutaneously to mice of 100 or 200 micromoles per kg. of levo-propoxyphene produced primarily an intensification of the analgesic effect of the dextro-enantiomer also administered subcutaneously. It was also reported on Apr. 15, 1975, at the annual meeting of the Federated American Society for Experimental Biologists, Atlantic City, N.J., by Murphy et al. that co-administration of equal amounts of 1-propoxyphene with a d-propoxyphene dose of 10 mg./kg. orally resulted in increased circulating plasma levels of d-propoxyphene 15 minutes after administration and that the administration of l-propoxyphene also enhanced the analgesic activity of d-propoxyphene. (Murphy et al. were using the name d-propoxyphene as a synonym for propoxyphene as used in the U.S. Pharmacopeia in order to differentiate it from l-propoxyphene which is the U.S. Pharmacopeia name for this compound, marketed as an antitussive as the napsylate salt), Murphy et al. further reported that the combination of d- and l-propoxyphene at 10 mg./kg. of each enantiomorph was found to have activity equivalent to that observed with d-propoxyphene alone at a 20 mg/kg. dose orally. In each instance, maximum analgesic effects were observed 15 minutes after administration of both drugs by the oral route.